Premium
ASIC1‐dependent Ca 2+ influx is required for NFATc3 activation in chronic hypoxia‐induced pulmonary hypertension (1090.12)
Author(s) -
Jernigan Nikki,
Plomaritas Danielle,
Giermakowska Wieslawa,
Herbert Lindsay,
Nitta Carlos,
Gonzalez Bosc Laura
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1090.12
Subject(s) - pulmonary hypertension , hypoxia (environmental) , medicine , right ventricular hypertrophy , endocrinology , chemistry , oxygen , organic chemistry
The development of chronic hypoxia (CH)‐induced pulmonary hypertension is associated with 1) the activation of the Ca 2+ ‐dependent transcription factor, nuclear factor of activated T‐cells isoform c3 (NFATc3), and 2) enhanced acid sensing ion channel 1 (ASIC1)‐dependent Ca 2+ influx in pulmonary arterial smooth muscle cells (PASMC). Therefore, we hypothesize that ASIC1‐mediated Ca 2+ influx increases NFATc3 nuclear translocation in pulmonary vascular smooth muscle. To test this hypothesis we first examined the effect of ASIC1 inhibition on NFATc3 nuclear translocation in PASMC in response to endothelin‐1 (ET‐1; 10 ‐7 M). Inhibition of ASIC1 with psalmotoxin‐1 (20 nM) diminished ET‐1 induced Ca 2+ influx and NFATc3 nuclear import. In addition, ET‐1 mediated pulmonary arterial vasoconstriction and Ca 2+ influx following CH (1 wk @ 380 mmHg) were blunted in ASIC1 knockout mice (ASIC1 ‐/‐ ) compared to the ASIC1 wildtype mice (ASIC1 +/+ ). Similarly, CH increased pulmonary vascular smooth muscle NFATc3 nuclear translocation in ASIC1 +/+ mice, but not in ASIC1 ‐/‐ mice. These CH‐induced responses were additionally associated with decreased right ventricular systolic pressure and right ventricular hypertrophy in ASIC1 ‐/‐ mice. Taken together, these data suggest that ASIC1‐dependent Ca 2+ influx is required for the activation and nuclear translocation of NFATc3 during the development of pulmonary hypertension. Grant Funding Source : Supported by R01 HL92598, R01 HL111084, T32 HL07736, R01HL088151, R01 HL088192